Throughout this application, various publications are referenced by Arabic numerals in parentheses. The disclosures of these publications in their entirety are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Mitomycin-C (MC), an antineoplastic agent used in clinic for treatment of cancer has been the subject of chemical synthesis and modification due to its potent activity and intriguing chemical structure (1). This antibiotic is now known to act as a bifunctional alkylating agent that crosslinks to DNA, after a series of biotransformations (2). MC is able to bind covalently at the minor groove of DNA double strand forming interstrand cross-links at two diagonally opposed deoxyguanosine (dG) residues in a CpG or GpC sequence (3, 4).
Recently, Archer, et al., synthesized lucanthone and its derivatives, and found that these compounds exhibited potent antischistosomal and antitumor activity (5). They also reported that lucanthone is capable of intercalating into DNA and monoalkylating the DNA to give a covalently bound drug-DNA complex after bio-oxidation. More recently, it was found that the inactive natural products, chrysophanol and emodin, can be converted into potently active agents against certain tumor cell growth by addition of an akylating side chain functionality to the molecule (6), which would enable these compounds to intercalate into and then alkylate DNA. Although attempts have been made to develop antitumor agents possessing both alkylating and intercalating capabilities, development of synthetic intercalators with cross-linking potential and potential as antitumor agents is novel.
We have designed and synthesized cross-linking alkylating agents similar to MC and MC analogues with alkylation and intercalation potential. This specification describes the synthesis of derivatives of 2,3-dihydro-1H-benz[e]inden-4,9-dione(cyclopentnaphthoquinone) and 2,3-dihydro-1H-cyclopent[a]anthracene-6,11-dione(cyclopentanthraquinone), which bear both an alkylating side chain, such as a mustard or alkyl carbamate side-chain and an aziridine-ring. Both cyclopentnaphthoquinone and cyclopentanthraquinone derivatives, like MC, may undergo bio-reduction to the corresponding hydroquinones, which would make the C-3 position susceptible to nucleophilic attack by DNA by opening the aziridine ring. The alkylating function on C-4 would bind to another part of DNA resulting in the formation of a cross-linked DNA-drug conjugate. Compounds with hydroxymethyl carbamate (--CH.sub.2 --OCONR'R") group at C-4, like MC, would form active quinone methide, which would be also susceptible to nucleophilic attack by DNA, after elimination of HO--CONHR. These cyclopentanthraquinone derivatives, unlike MC, would intercalate into DNA, and, similar to MC, may cross-link with DNA. The chemical synthesis of the new MC analogues as well as their biological activities has not been reported to date.